1. Field of the Invention
This invention relates to methods of using L-type calcium channel antagonists to treat arthritis.
2. Description of the Prior Art
Rheumatoid arthritis is a debilitating disease of the connective tissue. It most often manifests itself through inflammation and thickening of the synovial membranes, the sacs that hold the fluid (synovial fluid) that lubricates the joints. It generally causes irreversible damage to the joint capsule and the articular cartilage. There is evidence that suggests that an autoimmune mechanism may play a role in the disease.
Synovium is composed of two cell types termed type A synoviocytes and type B synoviocytes. (Gay and Gay, Rheumatol Int. 9, 105-113 (1989); Kouri et al., Scand. J. Immunol 19, 359-364 (1984); Burmester et al., Scand. J. Immunol. 17, 68-82 (1983)). Type A synoviocytes resemble tissue macrophages and type B synoviocytes resemble fibroblasts. Certain examples of tissue macrophage-like cells and fibroblasts possess calcium channels that resemble L-type calcium channels. Baumgarten and Villereal, J. Biol. Chem. 267, 10524-10530 (1992); Bernini et al., J. Cardiovasc. Pharmacol. 18, 42-45 (1991); Hijioka et al., Mol. Pharmacol. 41, 435-440 (1992); Kong et al., Second Messenger Phosphoproteins 13, 117-130 (1991); Olsen et at. Biochem. Biophys. Res. Commun. 162, 448-455 (1989). The evidence that suggests that certain macrophage- or fibroblast-like cells have L-type calcium channels includes: 1 ) electrophysiologic studies, 2) inhibition of calcium currents by selective L-type calcium channel antagonists, and 3 ) activation of calcium currents by selective L-type calcium channel agonists. In rheumatoid arthritis, type A cells and type B cells participate in the inflammatory process.
A hallmark of rheumatoid arthritis is the formation of a "pannus," which results from massive proliferation of synoviocytes. Synoviocytes are known to release inflammatory cytokines and other mediators as well as proteases and other enzymes that contribute to the tissue destruction associated with rheumatoid arthritis. Dayer and Demczuk, Cytokines and Other Mediators in Rheumatoid Arthritis, Springer Seminars in Immunopathology. 1-27 (Springer-Verlag 1984); Gay and Koopman, Current Opinion in Rheumatology 1, 8-14 (1989); Brennan et al., The Lancet Jul. 29, 224-247 (1989).
Adjuvant-induced arthritis is an experimental disease unique to laboratory rats. It occurs after inoculation with an oily emulsion or suspension of material possessing Freund's type adjuvant activity. Adjuvant-induced arthritis is a widely-used model for studying the physiology, biochemistry, and pharmacology of inflammation as well as a model of cell-mediated autoimmune disease, human arthritis, and chronic pain. Taurog et al., Meth. Enzymol 162, 339-355 (1988). As a model system, adjuvant arthritis has predicted clinical potency and efficacy for non-steroidal anti-inflammatory drugs NSAIDs used for rheumatoid arthritis. This is also the case for immunosuppressive agents, such as cyclosporin, and cytotoxic agents such as cyclophosphamide or methotrexate. Except for methotrexate, this latter class of drugs is not widely used for the treatment of rheumatoid arthritis because of problems with toxicity. A certain level of toxicity is also associated with the use of NSAIDs. Otterness and Bliven, Nonsteroidal Anti-inflammatory Drugs 111-252 (1985). The most common and perhaps most severe side effect is gastrointestinal bleeding. For example, ulceration of the upper gastrointestinal tract leading to gastrointestinal bleeding is common with therapeutic doses of indomethacin used in the treatment of rheumatoid arthritis. This is also the case for other NSAIDs.
Methotrexate has recently been approved for the treatment of severe, active rheumatoid arthritis. Hepatic fibrosis and cirrhosis have been reported in patients being treated for rheumatoid arthritis with methotrexate, however. There has also been evidence of progressive dose-related hepatic changes during extended periods of treatment that correlates with ethanol ingestion.
Indomethacin was introduced in 1963 to treat rheumatoid arthritis. Although it is widely used because of its efficacy, toxicity often limits its use. From 35 to 50 percent of patients receiving standard therapeutic doses of indomethacin experience untoward side effects, and about 20 percent are forced to discontinue its use.
The drug sulindac was developed in an attempt to find an effective, but less toxic alternative to indomethacin. It is only half as potent as indomethacin, however, and has toxic side effects of its own.
In view of the foregoing, alternative methods for the treatment of rheumatoid arthritis are desirable.